Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

Abstract

Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role in shaping the tumor microenvironment through a comprehensive analysis of multiple datasets, including 2,072 ccRCC samples. Unsupervised consensus clustering identified three senescence subtypes, and we found that the senescence-activated subtype survived the worst, even in the condition of targeted therapy and immunotherapy. The activated senescence program was correlated to increased genomic instability, unbalanced PBMR1/BAP1 mutations, elevated immune cell infiltration, and enhanced immune inhibitory factors (cancer-associated fibroblasts, immune suppression, immune exclusion, and immune exhaustion signaling). A senescence score based on nine senescence-related genes (i.e., P3H1, PROX1, HJURP, HK3, CDKN1A, AR, VENTX, MAGOHB, and MAP2K6) was identified by adaptive lasso regression and showed robust prognostic predictive power in development and external validation cohorts. Notably, we found that the senescence score was correlated to immune suppression, and the low-score subgroup was predicted to respond to anti–PD-1 therapy, whereas the high-score subgroup was predicted to respond to Sunitinib/Everolimus treatment. Collectively, senescence acted as an active cancer hallmark of ccRCC, shaped the immune microenvironment, and profoundly affected tumor prognosis and drug treatment response.

Identification of cell senescence molecular subtypes in prediction of the prognosis and immunotherapy of hepatitis B virus-related hepatocellular carcinoma

“…This is one of the reasons why the C2 subtype has a worse prognosis than the C1 subtype. This phenomenon was consistent with previous reports that identified the manifestation of senescent subtypes of clear cell renal cell carcinoma (33).…”

Interaction of RARRES1 with ICAM1 modulates macrophages to suppress the progression of kidney renal clear cell carcinoma

“…The characteristic of tumor microenvironment strongly influence disease biology and may influence the response rate to systemic therapy. Targeted immunotherapy is currently an option in first line treatment because KIRC is also considered an immunogenic tumour with high numbers of immune cells ( 4 ). Macrophage infiltration in KIRC is associated with prognosis ( 5 ).…”

Establishment of a new prognostic risk model of MAPK pathway-related molecules in kidney renal clear cell carcinoma based on genomes and transcriptomes analysis

“…Our study confirmed the differential expression of MAP2K6 in KIRC, which suggests its possible involvement in the biological processes of ccRCC. Recent study confirms MAP2K6 as senescence-related genes in ccRCC may influence the efficacy of anti-PD-1 therapy and Sunitinib/Everolimus treatment (43). Related studies have confirmed that activation of the Ras-MAPK pathway promotes immune evasion of tumor cells, proving that many associated molecules of the MAPK signaling pathway are significantly correlated with immune cell infiltration.…”